ABSTRACT/SUMMARY The accumulation of tau pathology in the brain is a defining feature of Alzheimer?s disease (AD) and related tauopathies. Over the last decade, histone deacetylase inhibitors (HDACi) have emerged as potential therapies to alleviate behavioral and cognitive deficits. However, given that HDACs are essential for a variety of cellular functions in the brain, their inhibition could pose unknown risks to humans subject to prolonged HDACi treatment. The cytoplasmic deacetylase HDAC6 is particularly relevant as a target of HDACi, as acute exposure to HDAC6-specific inhibitors is associated with restored cognitive function in AD mouse models. Recently, however, tau was shown to be extensively modified by lysine acetylation, and we implicated HDAC6 as a major tau deacetylase. Of particular concern, HDAC6 inhibition leads to acetylated tau accumulation, which is associated with MT instability, accelerated tau aggregation, synaptic defects, and AD-like cognitive impairments. Therefore, in stark contrast to the current notion of neuroprotection, we hypothesize that chronic long-term HDAC6 inhibition increases acetylated tau levels in the brain and therefore triggers tau-mediated neurodegeneration. This issue has major public health implications since pan-HDAC inhibitors (many of which target HDAC6) are now in clinical and preclinical use to treat a range of human disorders. In Aim-1 we will test the hypothesis that HDAC6 depletion in a tauopathy mouse model is sufficient to accelerate, not alleviate, tau pathology and neurodegeneration using histological, biochemical, and mouse behavioral approaches. Our preliminary data support an increase in acetylated tau levels and enhanced neurodegeneration in mice lacking HDAC6. In Aim-2, we will characterize newly generated mice lacking HDAC6 specifically in either neurons or microglia to establish whether HDAC6 loss enhances tau pathology in a cell autonomous or non-cell autonomous manner. Overall, our study will provide the first new insights into the pathological implications of sustained HDAC6 inactivation in the brain. Furthermore, our study could lead to future efforts to limit the use of FDA-approved HDAC inhibitors and consider alternative strategies to prevent the accumulation of acetylated tau pathology in the aged or AD brain.